Project Summary: In this competing renewal application, we will critically test a gene excision cure approach followed by neurorestoration therapy as a strategy to remove the HIV-1 provirus from the brain and promote neurocognitive recovery. Furthermore, efficacy of cure/restoration may be tailored for both males and females, as well as for those with a history of cocaine abuse. The hypothesis is that gene excision and estrogen/soy isoflavone therapy will restore neurocognitive function and synaptic complexity from the progressive decline characteristic of HIV-1 associated neurocognitive disorders (HAND). Thus, estrogenic compounds may serve as neurorestorative agents for the combined effects of cocaine/HIV proteins on producing synaptic impairments in the nucleus accumbens and prefrontal cortex, critical brain regions involved in the cognitive dysfunction associated with HAND. The specific aims are: 1) To establish efficacious neurorestoration of HIV-1/ cocaine-induced synaptopathy. The proposed in vitro experiments will establish neurorestoration at the synaptic level following both provirus activation and HIV-1 gene excision strategies. Novel compounds will be examined for neurorestoration of HIV-1 protein induced synaptopathy following cure strategies, with and without cocaine co-exposures, in sex-specified cell cultures. 2) To establish recovery from executive function deficits in HIV-1 transgenic animals, and the role of biological sex, with gene excision/ neurorestorative therapies. The ability to restore the neurocognitive/pathological consequences of HIV-1 proteins will be determined using assessment of executive function and synaptic plasticity/dendritic spines. Investigations will focus on quantifying spine density changes with respect to regulators of nucleus accumbens medium spiny neurons and prefrontal cortical neuronal plasticity. 3) To establish neurocognitive recovery in HIV-1 Tg animals, with deficits exacerbated by a history of cocaine abuse, with gene excision/ neurorestoration therapies. A critical in vivo test of gene excision/neurorestoration therapies will be provided with HIV-1 Tg animals that have an acquired history of cocaine self-administration; cocaine may accelerate the progression of HAND in HIV-1 infected patients by disrupting frontal cortex-nucleus accumbens circuitry. The robustness and generality of neurorestoration will subsequently be tested with self-administration of other abused substances (e.g. methamphetamine and methylphenidate). We are in a unique position to establish the trajectory of neurocognitive decline and synaptodendritic loss consequent to chronic HIV-1 protein/provirus expression and critically test a gene excision/regenerative-based therapeutic approach to protect and/or restore synaptodendritic complexity and neurocognitive function.